Carfilzomib公司
医学
癌症研究
外体
小RNA
多发性骨髓瘤
微泡
骨髓
间充质干细胞
免疫印迹
转移
下调和上调
干细胞
多效蛋白
生长因子
免疫学
病理
硼替佐米
细胞生物学
生物
癌症
内科学
基因
生物化学
受体
作者
Shifeng Long,Shengping Long,Hao He,Liang Luo,Chang-Jiu Li,Ting Ding
标识
DOI:10.1186/s13018-023-04399-9
摘要
Abstract Background Multiple myeloma (MM) is a common hematological malignancy. Drug resistance remains to be a major clinical challenge in MM therapy. In this study, we aim to investigate the functional roles of bone marrow mesenchymal stem cells (BMSC)-derived exosomal miR-182 on the carfilzomib resistance of MM and its underlying mechanism. Methods qRT-PCR and Western blot methods were utilized to confirm the gene or protein expressions. CCK-8 and transwell assays were performed to measure the capabilities of proliferation, migration, and invasion. The molecular interactions were validated through ChIP and Dual luciferase assay. Results Our findings indicated that miR-182 expression was upregulated in serum, BMSCs and BMSC-derived exosomes from MM patients. Hypoxia-inducible factor-1α (HIF-1α), a key transcriptional factor in tumor microenvironment, could boost miR-182 expression by directly binding to its promoter, thus favoring exosomal secretion. Moreover, exosomal miR-182 from BMSCs could be transferred to MM cells and was able to promote malignant proliferation, metastasis, and invasion, as well as decrease the sensitivity of MM cells against carfilzomib. Additionally, SOX6 was identified as a downstream target of miR-182 in MM cells, and its expression was negatively regulated by miR-182. Rescue experiments proved that loss of SOX6 in MM cells dramatically reversed the promoting roles of BMSC-secreted exosomal miR-182 on proliferation, metastasis, and carfilzomib resistance in MM cells. Conclusion Collectively, our findings indicated that exosomal miR-182 derived from BMSCs contributed to the metastasis and carfilzomib resistance of MM cells by targeting SOX6. This study sheds light on the pathogenesis of the BMSC-derived exosome containing miR-182 in the malignant behaviors of MM cells and carfzomib resistance.
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